One-pot solvent-free synthesis of novel functionalized ethyl 2-(alkylimino)-4-methyl-3-(alkanoyl)-2,3-dihydrothiazole-5-carboxylates

Article abstract of DOI:10.1002/jccs.201800018

A green and efficient one-pot two-step synthesis of ethyl 2-(alkylimino)-4-methyl-3-(alkanoyl)-2,3-dihydrothiazole-5-carboxylates from the reaction between acyl chlorides, ammonium thiocyanate, primary alkylamines, and ethyl 2-chloroacetoacetae under mild

Full text of DOI:10.1002/jccs.201800018

Received: 13 January 2018
Revised: 13 March 2018
Accepted: 24 March 2018
DOI: 10.1002/jccs.201800018
A R T I C L E
One-pot solvent-free synthesis of novel functionalized ethyl
-(alkylimino)-4-methyl-3-(alkanoyl)-2,3-dihydrothiazole-5-
2
carboxylates
1
2
1
Nasir Iravani | Mosadegh Keshavarz | Fatemeh Hosseini
1
Department of Chemistry, Gachsaran Branch,
A green and efficient one-pot two-step synthesis of ethyl 2-(alkylimino)-4-
methyl-3-(alkanoyl)-2,3-dihydrothiazole-5-carboxylates from the reaction
between acyl chlorides, ammonium thiocyanate, primary alkylamines, and ethyl
2-chloroacetoacetae under mild, solvent- and catalyst-free conditions at room
temperature is presented. This efficient and straightforward technique gave the
expected products in good to high yields in 2–4 hr without the creation of any
by-product in all reactions.
Islamic Azad University, Gachsaran, Iran
2
Department of Gas and Petroleum, Yasouj
University, Gachsaran, Iran
Correspondence
Nasir Iravani, Department of Chemistry,
Gachsaran Branch, Islamic Azad University,
Gachsaran 75818-63876, Iran.
Email: iravani.nasir@yahoo.com;
iravaninasir56@gmail.com
Mosadegh Keshavarz, Department of Gas and
Petroleum, Yasouj University, Gachsaran 75918-
KEYWORDS
7
4831, Iran.
green chemistry, one-pot reaction, solvent-free conditions, synthetic methods,
thiazole
Email: chem.mosadegh@gmail.com
1
| INTRODUCTION
and save time significantly. These reactions are suitable for
the synthesis of different classes of compounds and play an
One-pot synthesis is a strategy to improve the efficiency of
a chemical reaction whereby a reactant is subjected to suc-
cessive reaction steps in just one reactor. This is much
desired by chemists because avoiding a lengthy separation
process and purification of the intermediate chemical
compounds would save time and resources while increasing
the chemical yield.
One-pot reactions have emerged as a highly valuable
synthetic tool in the context of modern drug discovery. The
atom-economical and convergent character, the simplicity
of a one-pot procedure, the possible structural variations,
the accessible complexity of the molecules, and the very
large number of accessible compounds are among the
described advantages of one-pot reactions. Thus, they are
perfectly amenable to automation for combinatorial
synthesis.
important role in combinatorial chemistry because of their
ability to synthesize small drug-like molecules with several
degrees of structural diversity.
Small heterocyclic molecules play a critical role in the
search for new therapeutic and drug candidates and are
[
1]
essential to interpret the chemistry of living processes.
Among these compounds, thiazole derivatives show several
biological activities, for example, antimicrobial, anti-inflam-
[
2]
matory, antiviral, anti-tuberculosis, and cytotoxic.
[
3]
For instance, Ritonavir (an anti-HIV drug), Dasatinib
[
4]
and Tiazofurin (antineoplastic agents), Fanetizole, Fentia-
[
5]
zac, and Meloxicam (anti-inflammatory agents), Nizati-
[
6]
[7]
dine (antiulcer agent), Ravuconazole (antifungal agent),
[
8]
and Nitazoxanide (antiparasitic agent) are being used as
drugs (Figure 1). Because of the biological and pharmaceu-
tical importance of thiazole derivatives, several methods for
[
9–24]
With the rapid developments in the field of synthetic
organic chemistry, environmentally benign and eco-friendly
processes such as one-pot reactions are becoming more and
more in demand. One-pot reactions are fast and efficient
their synthesis have been developed.
We recently have combined three most attractive condi-
tions, namely one-pot, solvent-free, and noncatalytic, for the
[
25–30]
synthesis of novel thiazoles.
©
2018 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2018;1–6.
http://www.jccs.wiley-vch.de
1

2
IRAVANI ET AL.
At the first, the reaction condition was optimized. For
this purpose, the reaction of benzoyl chloride 1a, ammo-
nium thiocyanate 2,4-methyl benzylamine 3a, and ethyl 2-
chloroacetoacetate 4 was selected as a model reaction and
its behavior and progress were followed and studied under a
variety of conditions.
To do this, at the first step of the one-pot two-step reac-
tion, a round-bottomed flask containing each of the solvents
reported in Table 1 (even solvent-less) was charged with
equimolar amounts of benzoyl chloride and ammonium
thiocyanate. After 30 min of stirring, 3a and 4 were added.
The reactions were followed at both room temperature and
ꢀ
6
0 C for 3 hr. The results are summarized in Table 1.
From Table 1, solvent-free condition and room tempera-
ture gave the best result regarding the yield of the product
and the reaction time, giving the desired product in 90%
yield after stirring for 3 hr.
Therefore, solvent-free and room temperature were cho-
sen as the optimized condition with respect to the fast reac-
tion rate, high yield of the product, cheapness, green nature,
and environmental benignness. The product was isolated by
simple washing of the solid mass by water and was purified
by column chromatography to afford the desired pure thia-
zole compound 5a.
FIGURE 1 Thiazoles derivatives with biological activities
Next, using the optimized one-pot, solvent- and catalyst-
free conditions, the scope of this new one-pot reaction was
examined.
In continuation to our previous reports on the synthesis
of novel sulfur-containing organic compounds, here we
describe an efficient, green, and one-pot method involving
two consecutive steps for the synthesis of novel
functionalized 2,3-dihydrothiazole derivatives under mild,
solvent- and catalyst-free conditions (Scheme 1). This one-
pot two-step synthetic method furnishes the desired novel
functionalized 2,3-dihydrothiazoles in a straightforward,
facile procedure, and gives the pure target compounds con-
taining several potential centers for further modification.
To our surprise, we found that this transformation is
applicable for a wide range of different primary amines and
acyl chlorides providing an easy access to ethyl 2-(alkyli-
mino)-4-methyl-3-(alkanoyl)-2,3-dihydrothiazole-5-
carboxylates derivatives 5a–l in good to high yields
(80–95%) after purification. The results are summarized in
Table 2.
The identification of compounds 5a–l was done by ele-
1
13
mental analyses and their IR, H NMR, and C NMR
spectral data.
1
The H NMR spectrum of 5a in CDCl showed nine
3
2
| RESULTS AND DISCUSSION
signals for methyl (δ = 1.36, 2.32, and 2.6 ppm), OCH2
(
δ = 4.3 ppm), and NCH (δ = 5.56 ppm) protons along
2
In order to the synthesize the novel thiazole derivatives, we
focused our attention on a one-pot two-step reaction
between acyl chlorides 1, ammonium thiocyanate 2, primary
alkylamines 3, and ethyl 2-chloroacetoacetae 4 (Scheme 1).
with signals (δ = 7.14–7.15, 7.43, 7.48, and 8.31 ppm) for
the aromatic protons.
The C NMR spectrum of 5a showed 18 signals for the
methyl groups (δ = 12.81, 14.27, and 21.10 ppm), methy-
13
O
lene groups (δ = 49.28 ppm for CH N and δ = 61.19 ppm
2
NH SCN
4
O
for CH O) carbons, along with signals (δ = 110.10–
144.47 ppm) for the two olefinic and 12 aromatic carbons,
R1
Cl
2
OEt
1
2
Solvent- and Catalyst-free
r.t., 2-4 h
S
+
R2
which are in agreement with the proposed structure.
N
CH3
OEt
N
13
In addition, peaks in the C NMR spectrum of 5a at
NH2
Cl
O
O
1
R
1
61.82, 168.43, and 174.75 ppm are diagnostic for imino
R2
5
H C
3
O
and carbonyl groups, respectively. Partial assignments of
these resonances are given in the Experimental section.
A plausible mechanism for this reaction is given in
Scheme 2. It is initiated by the reaction of the acyl chloride
3
4
SCHEME 1 New one-pot, two-step route for the synthesis of novel
thiazole derivatives 5

IRAVANI ET AL.
3
TABLE 1 Optimization of the reaction condition for the one-pot synthesis
of ethyl 2-(4-methyl benzylimino)-4-methyl-3-(benzoyl)-2,3-
dihydrothiazole-5-carboxylate 5a
O
S
OEt
O
CH3
R1
Cl
O
+ NH SCN
4
Cl-
N
1
2
O
a
a
R1
NH
Time
(h)
Yield (%)
Yield (%)
+
H
ꢀ
ꢀ
Entry
Solvent
@ 25
C
@ 60
C
R2
OEt
S
O
1
2
3
4
5
6
7
8
H
2
O
3
3
3
3
3
3
3
3
0
27
O
8a
+
3
+4
R1
R2
R1
EtOH
15
35
48
50
70
76
90
38
N=C=S
N
N
O
H
H
Toluene
52
6
7
CH3
S
CH
CHCl
CH CN
2
Cl
2
70
Cl-
N
O
R2
NH
77
H
+
3
85
O
R1
3
8
b
EtOAc
84
Solvent-
free
94
O
OEt
O
OEt
CH
CH3
S
S
3
a
-HCl
Isolated yield.
O
OH
R1
R2
N
N
NH
R2
N
TABLE 2 Obtained results of the one-pot synthesis of thiazoles 5a–l
under optimized conditions
O
R
1
O
O
9
10
OEt
Time
(hr)
Yield
(%,gr)
m.
p. ( C)
S
1
2
ꢀ
CH
3
1
,3,5
R
C
C
R
-H
O
2
N
R2
N
a
6
6
H
H
5
5
4-Me–C
6
H
4
2.5
2
90, 0.36
85, 0.35
134–136
154–156
R1
O
b
4-MeO–
5
6 4
C H
c
C
6
H
5
2-Cl–C
6
H
4
4
2
4
88, 0.36
91, 0.41
187–190
159–162
SCHEME 2 Plausible mechanism for the synthesis of 2,3-dihydrothiazole
derivatives 5
d
2
4-NO –
4-MeO–
C H
6 4
C
6
H
4
e
f
4-Cl–C
6
H
4
2-Cl–C
4-F–C
4-MeO–
6
H
3
2
3
87,0.39
89, 0.35
93, 0.36
200–203
151–154
79–82
subsequent intramolecular cyclization produces the hetero-
C
6
H
5
6
H
4
cyclic intermediate 10, which generates 5 by the elimination
g
C(CH
3
)
3
[
29,30]
of water.
6 4
C H
h
C
6
H
5
CH
CH
3
–CH
2
2
–
4
90, 0.31
120–123
i
C(CH
C(CH
C(CH
3
)
3
)
3
)
3
3
3
C
6
H
5
3.5
3
81,0.29
95, 0.35
83, 0.26
80, 0.27
79–81
82–84
Oily
3 | EXPERIMENTAL
.1 | Chemicals and instrumentation
j
k
l
6 4
4-Me–C H
CH
3
–CH
2
2
3.5
3
3
C
6
H
5
CH
3
–CH
147–150
All of the chemicals were purchased from Fluka and Merck
in high purity and were used without further purification.
All the products were prepared using our own procedure
using the following apparatuses: mp: an Electrothermal
1
with ammonium thiocyanate 2 to give the acyl isothiocya-
nate 6. Then, the reaction of the intermediate 6 with the pri-
mary alkylamine 3 gives the unsymmetrical thiourea
derivatives 7. Subsequent regioselective nucleophilic alkyl-
ation of 7 with ethyl 2-chloroacetoacetate 4 yields the
intermediate 8b.
9
100 apparatus; IR spectra: a Shimadzu IR-460 spectrome-
1
13
ter with solid cell of KBr; H and C NMR spectra: Bruker
DRX-400 AVANCE instrument in CDCl at 400.13 and
3
1
00.61 MHz, respectively, with δ reported in ppm, and J in
Considering the higher nucleophilic power of nitrogen
hertz. Elemental analyses (C, H, and N) were performed
with a Heraeus CHN-O-Rapid analyzer. The analyzed data
were in agreement with the proposed structures.
2
1
in R –CH –NH compared to R –CO–NH, it is more reason-
able that the initial electron transfer on sulfur for alkylation
of 7 takes place via CH -NH.
2
2
Furthermore, considering the higher electrophilic prop-
erties of the carbon atom in CH–Cl compared with the car-
bonyl group and the softness of sulfur and CH, it seems
more reasonable that the alkylation of intermediate 7 takes
place in a regioselective manner via the initial attack of sul-
fur on CH–Cl. Therefore, the intermediate 8a cannot be
formed, and at this stage of the proposed mechanism the
reaction leads to the formation of the intermediate 8b. This
intermediate undergoes HCl elimination to give 9 and
3
.2 | General procedure for the preparation of
compounds 5a–l
In a typical procedure, 0.076 g of NH SCN 2 (1 mmol) was
4
added to a round-bottomed flask containing acyl chloride
1 (1 mmol), and the mixture was stirred at room tempera-
ture for 0.5 hr. Then, the primary amine 3 (1 mmol) and
ethyl 2-chloroacetoacetae 4 (1 mmol) were added and the
reaction mixture was stirred at room temperature. After

4
IRAVANI ET AL.
1
3
completion of the reaction as followed by TLC (2–4 hr; n-
hexane/AcOEt 3:1), water (5 mL) was added and the mix-
ture was stirred for 5 min. The precipitate was collected by
filtration and purified by column chromatography (silica gel
2CH) ppm; C NMR: δ = 12.49 (CH ), 14.27 (CH ),
3 3
46.67 (NCH ), 61.36 (OCH ), 110.36 (olefinic C), 126.83
2
2
(CH), 127.63 (CH), 128.11 (2CH), 129.17 (CH), 129.44
(2CH), 129.83 (CH), 131.93 (C), 132.25 (CH), 132.58 (C),
136.18 (C), 144.03 (olefinic C), 161.93 (C=N), 168.42
(C=O), 174.99 (C=O) ppm; Anal. Calc. for
C H ClN O S (414.9): C, 60.79; H, 4.62; N, 6.75; Cl,
230–240 mesh, Merck; n-hexane/AcOEt 4:1) to afford the
pure title compounds 5.
21
19
2 3
3
.2.1
| Ethyl 2-(4-methylbenzylimino)-4-methyl-3-benzoyl-
8
.55. Found: C, 60.82; H, 4.55; N, 6.81; Cl, 8.58%.
2,3-dihydrothiazole-5-carboxylate (5a)
Pale yellow powder; IR (KBr): ν = 3050 (CH arom), 2900
3.2.4 | Ethyl 2-(4-methoxybenzylimino)-4-methyl-3-(4-
nitrobenzoyl)-2,3-dihydrothiazole-5-carboxylate (5d)
(CH aliph), 1710, 1680 (C=O), 1600, 1568, 1540, 1470
(
6
C=C), 1260 (C=N), 1170, 1130, 1090, 910, 720,
Yellow powder; IR (KBr): ν = 3058 (CH arom), 2750
(CH aliph), 1710, 1680 (C=O), 1610, 1580, 1510, 1468
(C=C), 1280 (C=N), 1210, 1179, 1129, 1091, 910, 870,
−
1
1
3
90 cm ; H NMR: δ = 1.36 (3H, t, J = 6.8 Hz, CH3),
HH
2
.32 (3H, s, CH -Ph), 2.6 (3H, s, CH -vinylic), 4.3 (2H, q,
3
3
3
−1
1
3
JHH = 6.8 Hz, OCH ), 5.56 (2H, s, NCH ), 7.14–7.15
740, 760, 720 cm ; H NMR: δ = 1.38 (3H, t, J = 6.8
2
2
HH
3
(
(
2
4H, m, 4CH), 7.43 (2H, d, J = 7.2 Hz, 2CH), 7.48
1H, d, J = 7.2 Hz, CH), 8.31 (2H, d, JHH = 7.2 Hz,
CH) ppm; C NMR: δ = 12.81 (CH ), 14.27 (CH ), 21.1
Hz, CH ), 2.69 (3H, s, CH -vinylic), 3.79 (3H, s, OCH ),
HH
3
3
3
3
3
3
4.33 (2H, q, J = 6.8 Hz, OCH ), 5.6 (2H, s, NCH ),
HH 2 2
6.88 (2H, d, J = 7.2 Hz, 2CH), 7.22 (2H, d, J = 7.1
HH HH
Hz, 2CH), 8.27 (2H, d, J = 7.6 Hz, 2CH), 8.45 (2H, d,
HH
JHH = 7.6 Hz, 2CH) ppm C NMR: δ = 12.91 (CH3),
HH
1
3
3
3
3
3
3
(CH ), 49.28 (NCH ), 61.19 (OCH ), 110.1 (olefinic C),
3
2
2
3
13
1
1
26.96 (2CH), 128.11 (2CH), 129.4 (2CH), 129.69 (2CH),
31.82 (C), 132.32 (CH), 136.42 (C), 137.89 (C), 144.47
14.25 (CH ), 49.26 (NCH ), 55.34 (OCH ), 61.48 (OCH ),
3
2
3
2
(
olefinic C), 161.82 (C=N), 168.43 (C=O), 174.75 (C=O)
111.02 (olefinic C), 114.53 (2CH), 123.35 (2CH), 126.79
(2CH), 128.34 (2CH), 130.26 (C), 142.01 (C), 144.49 (ole-
finic C), 149.73 (C), 159.57 (C), 161.7 (C=N), 168.99
ppm; Anal. Calc. for C H N O S (394.49): C, 66.98; H,
5
2
2 22 2 3
.62; N, 7.10. Found: C, 66.92; H, 5.65; N, 7.13%.
(
(
4
C=O), 172.7 (C=O), ppm; Anal. Calc. for C H N O S
22 21 3 6
455.48): C, 58.01; H, 4.65; N, 9.23. Found: C, 57.97; H,
.68; N, 9.15%.
3
.2.2
| Ethyl 2-(4-methoxybenzylimino)-4-methyl-3-benzoyl-
2,3-dihydrothiazole-5-carboxylate (5b)
Pale yellow powder; IR (KBr): ν = 3060 (CH arom),
2
1
9
950–2850 (CH aliph), 1740, 1680 (C=O), 1600, 1558,
3.2.5 | Ethyl 2-(2-chlorobenzylimino)-4-methyl-3-(4-chloro
benzoyl)-2,3-dihydrothiazole-5-carboxylate (5e)
510, 1460 (C=C), 1280 (C=N), 1178, 1130, 1090,
−
1
1
80, 900, 860, 800, 720, 680 cm ; H NMR: δ = 1.36
Yellow powder; IR (KBr): ν = 3050 (CH arom),
3000–2850 (CH aliph), 1690, 1670 (C=O), 1600, 1580,
1559, 1520 (C=C), 1285 (C=N), 1220, 1210, 1180, 1165,
3
(3H, t, J = 7.2 Hz, CH ), 2.66 (3H, s, CH -vinylic),
HH 3 3
3
3
5
7
.78 (3H, s, OCH ), 4.31 (2H, q, J = 7.2 Hz, OCH2),
.57 (2H, s, NCH ), 6.86 (2H, d, J = 8.8 Hz, 2CH),
.25 (2H, d, J = 8.8 Hz, 2CH), 7.44 (2H, t, J = 7.6
3 HH
3
−1 1
1099, 990, 905, 879, 740, 768 cm ; H NMR: δ = 1.35
2
HH
3
3
3
(3H, t, J = 7.2 Hz, CH ), 2.61 (3H, s, CH -vinylic), 4.3
HH
HH
HH
3
3
3
3
Hz, 2CH), 7.51 (1H, t, J = 7.2 Hz, CH), 8.33 (2H, d,
JHH = 7.6 Hz, 2CH) ppm; C NMR: δ = 12.85 (CH3),
(2H, q, J = 7.2 Hz, OCH ), 5.56 (2H, s, NCH ), 7.02
HH 2 2
HH
3
13
3
3
(2H, t, J = 7.1 Hz, 2CH), 7.27 (1H, t, J = 7.2 Hz,
HH HH
3
3
1
1
4.24 (CH ), 48.99 (NCH ), 55.28 (OCH ), 61.2 (OCH ),
10.16 (olefinic C), 114.4 (2CH), 127.31 (2CH), 128.12
CH), 7.43 (2H, d, J = 7.6 Hz, 2CH), 7.5 (1H, t, J
7.2 Hz, CH), 8.28 (2H, d, J = 7.6 Hz, 2CH) ppm;
HH
=
C
3
2
3
2
HH
HH
13
3
(
(
(
(
2CH), 128.51 (2CH), 129.41 (C), 131.81 (C), 136.46
CH), 144.32 (olefinic C), 159.8 (C), 161.98 (C=N), 168.4
C=O), 174.85 (C=O) ppm; Anal. Calc. for C H N O S
410.49): C, 64.37; H, 5.40; N, 6.83. Found: C, 64.39; H,
.44; N, 6.79%.
NMR: δ = 8.03 (CH ), 9.48 (CH ), 43.99 (NCH ), 56.52
3 3 2
(OCH ), 105.57 (olefinic C), 111.16 (CH), 111.37 (CH),
2
123.4 (CH), 124.07 (2CH), 124.15 (C), 124.6 (2CH),
126.38 (CH), 127.16 (C), 131.54 (C), 139.29 (C), 156.44
(olefinic C), 158.09 (C=N), 163.66 (C=O), 170.02 (C=O)
ppm; Anal. Calc. for C H Cl N O S (449.35): C,
2
2 22 2 4
5
21
18
2 2 3
3
2
.2.3
| Ethyl 2-(2-chlorobenzylimino)-4-methyl-3-benzoyl-
5
4
6.13; H, 4.04; N, 6.24; Cl, 15.78. Found: C, 56.08; H,
.10; N, 6.19; Cl, 15.81%.
,3-dihydrothiazole-5-carboxylate (5c)
Pale yellow powder; IR (KBr): ν = 3050 (CH arom),
2
1
9
990–2800 (CH aliph), 1704, 1682 (C=O), 1600, 1568,
3.2.6
| Ethyl 2-(4-fluorobenzylimino)-4-methyl −3-benzoyl-
2
,3-dihydrothiazole-5-carboxylate (5f)
470 (C=C), 1272 (C=N), 1218, 1175, 1130, 1098,
−1
1
80, 998, 918, 875, 748, 718 cm ; H NMR: δ = 1.39
Yellow powder; IR (KBr): ν = 3050 (CH arom),
2995–2900 (CH aliph), 1690, 1680 (C=O), 1600, 1564
(C=C), 1261 (C=N), 1098, 1060, 990, 905, 710, 700,
684 cm ; H NMR: δ = 1.36 (3H, t, J = 7.2 Hz, CH ),
HH 3
2.61 (3H, s, CH -vinylic), 4.34 (2H, q, JHH = 7.2 Hz,
3
3
(
(
(
3H, t, J = 7.2 Hz, CH ), 2.6 (3H, s, CH -vinylic), 4.34
HH 3 3
2H, q, J = 7.2 Hz, OCH ), 5.75 (2H, s, NCH ), 6.78
1H, d, J = 7.6 Hz, CH), 7.18 (1H, t, J = 7.2 Hz,
3
HH
2
2
3
3
−1
1
3
HH
HH
3
3
CH), 7.39–7.48 (5H, m, 5CH), 8.25 (2H, d, J = 7.6 Hz,
HH

IRAVANI ET AL.
5
OCH ), 5.73 (2H, s, NCH ), 6.76–6.77 (1H, m, CH),
δ = 12.58 (CH ), 14.29 (CH ), 28.12 (3CH ), 41.27 (C),
49.31 (NCH ), 61.39 (OCH ), 110.52 (olefinic C), 125.61
2 2
2
2
3
3
3
7.17–7.2 (1H, m, CH), 7.26–7.28 (2H, m, 2CH), 7.37–7.38
(
2
4
2H, m, 2CH), 7.46–7.49 (1H, m, CH), 8.15–8.18 (2H, m,
CH) ppm; C NMR: δ = 12.51 (CH ), 14.26 (CH ),
3 3
(CH), 128.12 (2CH), 129.33 (2CH), 138.4 (C), 144.22 (ole-
finic C), 161.46 (C=N), 168.29 (C=O), 174.12 (C=O) ppm;
Anal. Calc. for C H N O S (360.47): C, 63.31; H,
13
6.73 (NCH ), 61.43 (OCH ), 110.57 (olefinic C), 126.74
2
2
19 24 2 3
(
(
(
2CH), 127.65 (2CH), 128.36 (2CH), 129.25 (2CH), 129.88
CH), 130.83 (C), 134.71 (C), 138.12 (olefinic C), 144.01
C), 161.83 (C=N), 168.52 (C=O), 174 (C=O) ppm; Anal.
6
.71; N, 7.77. Found: C, 63.26; H, 6.64; N, 7.82%.
3.2.10
| Ethyl 2-(4-methylbenzylimino)-4-methyl-3-pivaloyl-
2
,3-dihydrothiazole-5-carboxylate (5j)
Calc. for C H FN O S (398.45): C, 63.32; H, 4.81; N,
21
19
2 3
7.03; F, 4.77. Found: C, 63.25; H, 4.76; N, 7.11; F, 4.84%.
Pale yellow powder; IR (KBr): ν = 3068 (CH arom),
985–2890 (CH aliph), 1736, 1695 (C=O), 1600, 1580,
3
.2.7
|
Ethyl 2-(4-methoxybenzylimino)-4-methyl-3-pivaloyl-
−1
545 (C=C), 1268 (C=N), 1090, 910, 745, 690, 655 cm ;
2,3-dihydrothiazole-5-carboxylate (5g)
3
3
HH
Pale yellow powder; IR (KBr): ν = 3048 (CH arom),
2
1
3
3
3
950–2900 (CH aliph), 1700, 1680 (C=O), 1610, 1556,
508 (C=C), 1260 (C=N), 1099, 910, 710, 700, 759,
40 cm ; H NMR: δ = 1.27 (9H, s, 3CH ), 1.32 (3H, t,
3
3
3
HH
13
HH
−
1 1
6
3
3
3
3
JHH = 7.2 Hz, CH ), 2.63 (3H, s, CH -vinylic), 3.79 (3H,
3
3
3
s, OCH ), 4.27 (2H, q, J = 7.2 Hz, OCH ), 5.42 (2H, s,
3
HH
2
2
3
NCH ), 6.85 (2H, d, J = 8.0 Hz, 2CH), 7.2 (2H, d,
2
HH
3
13
JHH = 8.0 Hz, 2CH) ppm; C NMR: δ = 12.83 (CH3),
4.2 (CH ), 27.71 (3CH ), 40.88 (C), 48.76 (NCH ), 55.31
1
3
3
2
20 26 2 3
(OCH ), 61.06 (OCH ), 109.49 (olefinic C), 114.25 (2CH),
3 2
9.05; H, 7.16; N, 7.53%.
1
1
27.49 (2CH), 128.57 (C), 134.99 (olefinic C), 159.39 (C),
62.17 (C=N), 168.19 (C=O), 189.5 (C=O) ppm; Anal.
Calc. for C H N O S (390.5): C, 61.51; H, 6.71; N, 7.18.
20
26
2
4
Found: C, 61.58; H, 6.65; N, 7.22%.
Yellow oil; IR (KBr): ν = 3000–2880 (CH aliph), 1750,
1
9
655 (C=O), 1600, (C=C), 1268 (C=N), 1120, 1090, 1045,
10, 850, 710, 690 cm ; H NMR: δ = 0.98 (3H, t,
3
.2.8 | Ethyl 2-(butylimino)-4-methyl-3-benzoyl-2,3-dihydro
−
1
1
thiazole-5-carboxylate (5h)
3
JHH = 7.2 Hz, CH ), 1.26 (9H, s, 3CH ), 1.32 (3H, t,
3
3
Pale yellow powder; IR (KBr): ν = 3060 (CH arom),
2
1
3
3
JHH = 7.2 Hz, CH ), 1.77 (2H, six, J = 7.2 Hz, CH2),
3
HH
950–2850 (CH aliph), 1780, 1650 (C=O), 1598, 1560,
3
2
.68 (3H, s, CH -vinylic), 4.14 (2H, t, J
= 7.1 Hz,
HH
3
489, 1470 (C=C), 1280 (C=N), 1143, 1089, 1038,
3
13
−
1
1
NCH
NMR: δ = 11.28 (CH
(CH ), 27.71 (3CH ), 40.81 (C), 47.7 (NCH
OCH ), 109.22 (olefinic C), 143.61 (olefinic C), 162.28
2
), 4.27 (2H, q, JHH = 7.2 Hz, OCH
) ppm;
2
C
9
20, 860, 720, 680 cm ; H NMR: δ = 1.03 (3H, t,
3
3
), 12.51 (CH
3
), 14.19 (CH
3
), 21.74
3
JHH = 7.2 Hz, CH ), 1.37 (3H, t, J = 7.2 Hz, CH ),
3
HH
3
3
3
2
3
), 60.99
2
1
7
.48 (2H, six, J = 7.6 Hz, CH ), 1.82 (2H, qui, J
=
HH
2
HH
(
(
2
.2 Hz, CH ), 2.74 (3H, s, CH -vinylic), 4.29–4.35 (4H,
2
3
C=N), 167.31 (C=O), 189.32 (C=O) ppm; Anal. Calc. for
m, NCH and OCH ), 7.45–7.54 (3H, m, 3CH), 8.32 (2H,
d, J = 7.6 Hz, 2CH) ppm; C NMR: δ = 12.55 (CH3),
1
2
2
3
13
C H N O S (312.43): C, 57.66; H, 7.74; N, 8.97.
15 24 2 3
Found: C, 57.76; H, 7.68; N, 8.89%.
HH
3.75 (CH ), 14.26 (CH ), 20.15 (CH ), 29.71 (CH ), 46.31
3 3 2 2
(
1
1
NCH ), 61.13 (OCH ), 109.91 (olefinic C), 128.09 (2CH),
29.03 (2CH), 131.72 (C), 136.6 (CH), 143.91 (olefinic C),
62.08 (C=N), 167.57 (C=O), 174.65 (C=O) ppm; Anal.
2 2
3
.2.12 | Ethyl 2-(propylimino)-4-methyl-3-benzoyl-2,3-
dihydro thiazole-5-carboxylate (5l)
Pale yellow powder; IR (KBr): ν = 3050 (CH arom), 2900
Calc. for C H N O S (346.45): C, 62.43; H, 6.45; N,
8
18 22 2 3
(CH aliph), 1680, 1650 (C=O), 1598, 1560, 1470 (C=C),
.09. Found: C, 62.29; H, 6.47; N, 8.16%.
−
1 1
1
285 (C=N), 1158, 1090, 958, 720, 678 cm ; H NMR:
3
3
δ = 1.04 (3H, t, J = 7.2 Hz, CH ), 1.36 (3H, t, J =
HH
7.2 Hz, CH
3
.2.9
|
Ethyl 2-(benzylimino)-4-methyl-3-pivaloyl-2,3-
HH
3
3
dihydro thiazole-5-carboxylate (5i)
), 1.87 (2H, six, JHH = 7.6 Hz, CH ), 2.71
3 2
(
7
3H, s, CH -vinylic), 4.24–4.31 (4H, m, NCH and OCH ),
Pale yellow powder; IR (KBr): ν = 3051 (CH arom),
3
2
2
3
.34–7.51 (3H, m, 3CH), 8.31 (2H, d, J = 7.2 Hz, 2CH)
2
960–2920 (CH aliph), 1728, 1685 (C=O), 1605, 1550,
HH
−1
13
1
510 (C=C), 1266 (C=N), 1096, 900, 730, 700, 640 cm ;
ppm; C NMR: δ = 11.35 (CH
(CH
(olefinic C), 128.08 (2CH), 129.28 (2CH), 131.71 (C),
136.58 (CH), 143.93 (olefinic C), 162.05 (C=N), 167.6
(C=O), 174.6 (C=O) ppm; Anal. Calc. for C H N O S
3
), 12.55 (CH ), 14.24
), 61.12 (OCH ), 109.86
2
3
1
3
H NMR: δ = 1.25 (9H, s, 3CH ), 1.34 (3H, t, J = 7.2
3
), 21.85 (CH
), 47.94 (NCH
2
2
3
HH
3
Hz, CH ), 2.65 (3H, s, CH -vinylic), 4.26 (2H, q, J =
HH
3
3
7
.1 Hz, OCH ), 5.45 (2H, s, NCH ), 7.53–7.62 (3H, m,
2
2
3 13
3CH), 7.73 (2H, d, J = 8.0 Hz, 2CH) ppm; C NMR:
HH
17 20 2 3

6
IRAVANI ET AL.
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| CONCLUSIONS
[
[
In conclusion, a new set of thiazole derivatives were synthe-
sized in a one-pot, two-step process from the reaction of
acyl chlorides, ammonium thiocyanate, primary alkyla-
mines, and ethyl 2-chloroacetoacetate. This new protocol
has several advantages such as the avoidance of the solvent
and catalyst, good to high yields of the target product, short
reaction times, the possibility of mixing the substances
without any activation or modification, and simple experi-
mental work-up. And reaction could be performed at room
temperature under neutral conditions by simple mixing of
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This work was partially supported by the Gachsaran
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